Future work should draw on longitudinal data to examine the ways in which the strength of associations for PRS changes with the age of the target sample. Third, UKB was a large portion of the discovery sample for each of the GWAS used to create PRS. To the degree that UKB is biased, each of the PRS in these analyses will also reflect that bias. Finally, these analyses examined the marginal influence of PRS, independent of environment. Processes of gene-environment interaction are well documented in alcohol misuse. Incorporating environmental information along with PRS in a methodologically rigorous manner will be an important next step in developing clinically predictive algorithms. Polygenic scores are becoming better powered and starting to explain non-trivial portions of variance. We examined the current state of PRS for substance use, with a focus on AUD. Each of the PRSs analyzed here were associated with AUD. However, the maximum variance explained by any single score was still small . Individuals at the top of the PRS continuum had elevated rates of multiple substance use problems, but these differences across the PRS continuum are unlikely to be of broad clinical use in their current state. As GWAS discovery samples become larger and we are better able to model the complex relationship between genotype and phenotype, polygenic scores may eventually be useful in a clinical setting.Caffeine reduces fatigue and increases concentration and alertness, and athletes regularly use it as an ergogenic aid.Trained athletes seem to benefit from a moderate dose of 5 mg/kg, however, flood tray even lower doses of caffeine may improve performance. Some groups found significantly improved time trial performance or maximal cycling power, most likely related to a greater reliance on fat metabolism and decreased neuromuscular fatigue, respectively.

Theophylline, a metabolite of caffeine, seems to be even more effective in doing so. The effect of caffeine on fat oxidation, however, may only be significant during lower exercise intensities and may be blocked at higher intensities. Spriet et al.found that ingestion of a high dose of caffeine before exercise reduced muscle glycogenolysis in the initial 15 min of exercise by increasing free fatty acid levels which inhibits glycolysis and spares glycogen for later use. Caffeine’s effect of inhibition of glycogen phosphorylase has also been shown in vitro as well as its effect on increasing HSL activity. The effect of caffeine on adipose triglyceride lipase has not been studied and warrants investigation. Following caffeine administration prior to and after the onset of cycling, Ivy et al. found that plasma free fatty acid levels were increased 30% compared to placebo. This action might be mediated by inhibition of the enzyme phosphodiesterase, thereby yielding higher levels of cAMP, which has been identified as important molecule for glycogen metabolism and lipolysis. Phosphodiesterase inhibition has been observed only at high concentrations. When direct Fick measurements were applied, Graham et al. did not find altered CHO or fat metabolism, at least in the monitored leg. Further research is needed to evaluate the effect of caffeine on lipolysis, especially during higher exercise intensities. Augmented post-exercise recovery by increased rates of muscle glycogen resynthesis has been observed. Pedersen et al. found higher rates of muscle glycogen accumulation after the co-ingestion of caffeine with CHO during recovery in highly trained subjects. This might, at least in part, be mediated by the activation of AMP-activated protein kinase as it is involved in the translocation of glucose transporter 4 to the plasma membrane. This mechanism enables the cell to take up glucose from the plasma and store it as glycogen.

Not only does caffeine impact endurance, it has also been reported to benefit cognitive function and fine motor skills. While the performance enhancing effects of caffeine in moderate-to-highly trained endurance athletes are quite clear and well documented, its effects on anaerobic, high-intensity tasks are less well investigated. Whereas caffeine supplementation did not yield significant performance increases in a Wingate test in untrained subjects, Mora-Rodriguez et al.report that caffeine ingestion of 3 mg/kg could counter reductions in maximum dynamic strength and muscle power output on the morning thereby increasing muscle performance to the levels found in the afternoon. Especially with regard to anaerobic performance caffeine’s adenosine receptor blocking effect in the CNS may be important. A possible explanation for the diverging effect of caffeine on anaerobic performance is that caffeine seems to benefit trained athletes who show specific physiological adaptations whereas performance gains in untrained subjects might be lost or masked by a high variability in performance. It has been shown that coffee, by containing phenolic compounds such as chlorogenic acids, elicits metabolic effects independent of caffeine. These compounds may have the potential to antagonize the physiological responses of caffeine. The question therefore remains whether ingesting the same amount of caffeine via a food source is as effective as ingesting isolated caffeine in the form of a tablet. As mentioned above, the performance enhancing effect of caffeine is very clear. Only a few studies, however, have shown a positive effect of coffee on performance. Whereas some studies found enhanced performance after coffee consumption, others did not. One of the earlier works by Costill et al. reported increases in time trial performance of competitive cyclists only in the coffee trial group but not in the decaffeinated coffee trial. Graham et al. studied exercise endurance in runners after ingestions of a caffeine or placebo capsule with water or either decaffeinated coffee, decaffeinated coffee with added caffeine or regular coffee. The authors found that only caffeine significantly improved running time to exhaustion at 75% VO2max but neither did regular coffee or decaffeinated coffee plus caffeine. Based on these results, the authors speculated that some component in coffee possibly interfere with the ergogenic response of caffeine alone.

This is in opposition to Hodgson et al.who looked at time trial performance in trained subjects after administration of caffeine , coffee , decaffeinated coffee and placebo one hour prior to exercise. The authors report similar significant increases of ~5% in time trial performance in both the caffeine and the coffee supplemented group with no effects in the decaf or placebo group. The authors conclude that coffee consumed 1 h prior to exercise, at a high caffeine dose improved performance to the same extent as caffeine. One reason for the disparity of the two studies mentioned above might be the different performance tests used. Whereas Graham et al. used a time to exhaustion test which reportedly can exhibit a coefficient of variation as high as ~27%, Hodgson et al. used a time trial which have been shown to be more reproducible. It has also been speculated by Hodgson et al. that due to lower statistical power, Graham et al. were not able to detect a difference between caffeine and coffee ingestion on performance. At this point, both coffee and caffeine exhibit a performance enhancing effect. Further research will hopefully extend our understanding on this issue. Another reason for the widespread use of caffeine within the exercise community might be its small but significant analgesic effect, possibly mediated by augmenting plasma endorphin concentrations. It is also established that caffeine reduces the rate of perceived exertion during exercise, suggesting that athletes are able to sustain higher intensities but do not perceive this effort to be different from placebo conditions. Some studies used caffeine-naïve whereas others used caffeine-habituated subjects. There seems to be a higher increase in plasma adrenalin in caffeine-naïves compared to caffeine habituated subjects after caffeine ingestion. However,grow table no differences between habitual caffeine intake and 1500 m running performance or force of contraction could be observed. For both caffeine-naïve as well as caffeine-habituated subjects, moderate to high doses of caffeine are ergogenic during prolonged moderate intensity exercise. Although there is clearly the need to study caffeine habituation further, the differences between users and non-users do not seem to be major.From 1962 to 1972 and again from 1984 to 2003 caffeine was on the WADA banned list, with a concentration >12 μg/ml in the urine considered as doping. Caffeine has been demonstrated to be ergogenic at doses lower than those doses that result in a urine concentration of 12 μg/ml, and higher doses appear to exhibit no additional performance-enhancing effect. During the second banned period, many athletes tested positive for caffeine. The sanctions ranged from warnings up to 2 year suspensions . Since 2004, caffeine has been removed from the prohibited list, however, it is still part of WADAs monitoring program in order to monitor the possible potential of misuse in sport. According to WADA, one of the reasons caffeine was removed from the Prohibited List was that many experts believe it to be ubiquitous in beverages and food and that having a threshold might lead to athletes being sanctioned for social or dietary consumption of caffeine. Furthermore, caffeine is metabolized at very different rates in individuals and hence urinary concentrations can vary considerably and do not always correlate to the dose ingested.

In addition, caffeine is added to a wide range of popular food products such as coffee, tea, energy drinks and bars, and chocolate.In general, nicotine has a psychostimulatory effect on the CNS at low doses via enhancing the actions of norepinephrine and dopamine in the brain. At higher doses, however, nicotine enhances the effect of serotonin and opiate activity, exerting a calming and depressing effect. Nicotine-induced stimulation of the sympathetic nervous system leads to increased heart rate and blood pressure, cardiac stroke volume and output and coronary blood flow. Although the results are conflicting and some authors report increases in cutaneous blood flow and skin temperature, others report a decrease in cutaneous blood flow and subsequent decline in skin temperature associated with nicotine consumption. These differences in cutaneous blood flow are possibly related to differences in nicotine administration. Both snus and nicotine gums enable nicotine to diffuse across the mucous membranes and are taken up by the bloodstream or, when inhaled, diffuses across the alveolar membrane of the alveoli, and enters the bloodstream. Although the amount of nicotine inhaled is lower than with conventional cigarettes, the use of electronic cigarettes is becoming more and more popular. However, the amount taken up by smokeless tobacco users tends to be much greater than by smoking. Once in the bloodstream, nicotine is quickly delivered to the brain, where it interacts with neural nicotinic acetylcholine receptors . It is metabolized by the liver cytochrome P450 enzyme system and has a half-life of approximately 2 hours. Upon binding of ACh or its exogenous ligand nicotine, the ion channel is opened and causes an influx of sodium and calcium . This local increase in intracellular Ca2+ can alter cellular functions. A mechanism termed Ca2+-induced Ca2+ release can further boost intracellular calcium upon activation of nAChR. In vitro experiments using human neutrophils showed a dose-dependent rise in intracellular Ca2+ levels of 700% over baseline at a concentration of 10-2 M nicotine. In numerous pathways, Ca2+ acts as an intracellular messenger, setting the stage for nAChRs as potent candidates to influence a variety of Ca2+-dependent neuronal processes, such as neurotransmitter release, synaptic plasticity or gene transcription.While it is clear that smoking can lead to the development of respiratory, cardiovascular, and skin diseases as well as a number of tobacco-related cancers there are other forms of application such as the use of alternative smokeless tobacco , which is gaining popularity among athletes as it bypasses the respiratory system. Snus and cigarette consumers show similar peak blood nicotine levels after use with a tendency for higher cotinine levels in the former. Nicotine activates the sympathoadrenal system, which leads to increased heart rate, contractility, vasoconstriction and a rise in blood pressure and the level of circulating catecholamines during light exercise. Nicotine also increases muscle blood flow and lipolysis due to enhanced circulating levels of norepinephrine and epinephrine as well as direct action on nicotinic cholinergic receptors in adipose tissue. The effects exerted by nicotine may be beneficial in a wide variety of sports and it is suggested that nicotine is abused by athletes. According to Marclay , cumulative exposure to nicotine metabolites were found in 26% – 56% of urine samples that were subjected to screening for tobacco alkaloids. After correcting for exposure to second-hand smoke, 15% of the athletes were considered active nicotine consumers.